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With MJFF funding, Jeff Conn, PhD, at Vanderbilt University has accelerated a promising new PD treatment toward the clinic. Instead of targeting the dopamine system, his approach focuses on the glutamate system, which could match the benefit of levodopa without triggering dyskinesias.

Appearing in the MJFF Winter 2011 newsletter, this article was the first in "The Fox Approach"--a recurring series highlighting MJFF's out-of-the-box approach to speed the cure. Stay tuned for more stories like this one!

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In December 2007, the Wall Street Journal reported on a troubling trend in drug development.

“Over the next few years the pharmaceutical business will hit a wall,” the paper wrote. In the modern era of complex disease, blue-chip drugmakers’ in-house research operations were bringing fewer and fewer therapies to market. Struggling to recoup their research investments in the development of new treatments that can cost over a billion dollars, more and more companies were downsizing these programs as part of major cost-cutting initiatives. For many, patents on the most profitable products in their portfolios were soon to expire.

“In five years,” the Journal predicted, “many [of these companies] may look very different. They will be in new businesses.”

Yet disease — and the need for new and better treatments to benefit countless human lives — marched on without regard to business objectives or shareholder return. To The Michael J. Fox Foundation (MJFF), with its relentless focus on speeding scientific breakthroughs for Parkinson’s disease (PD) and its habitual problem-solving approach, the need for out-of-the-box thinking had never been clearer. Promising alternative models were needed to supplement Big Pharma’s resources and decades of expertise in developing drugs — and to get off the ground, they would need significant support from funders willing to champion new approaches.

Meanwhile, a scientist at Vanderbilt University in Nashville, Tennessee, was quietly undertaking his own mission to drive the pharmaceutical pipeline forward. Jeff Conn, PhD, was a member of the Foundation’s Scientific Advisory Board and director of the Vanderbilt Center for Neuroscience Drug Discovery. Since 2003, Conn, a former senior director of neuroscience at Merck & Co., had worked to assemble a team of more than 60 scientists devoted to conducting the long and specific series of studies — traditionally the purview of industry, not academia — that could usher a drug into clinical testing. Conn also had a particular research interest in developing drugs to treat complicated neurological diseases, including PD.

“Jeff had come to the Foundation with a proposal to develop an entirely new class of treatment for Parkinson’s disease,” recalls Todd Sherer, PhD, the Foundation’s CEO. “He wanted to diverge from the classical pursuit of treatments targeting the dopamine system. His idea was to work within the glutamate system and bypass dopamine replacement altogether. The goal was to match the symptomatic benefit of levodopa while avoiding debilitating side effects like dyskinesias.”

With funding from the Foundation starting in 2005, Conn’s team at Vanderbilt had been screening drug compounds with potential to activate specific glutamate receptors implicated in Parkinson’s disease. The compounds worked in a fundamentally different way from dopamine replacement therapy, instead modulating another of the brain’s neurotransmitters, glutamate. Conn and his colleagues had been working to activate a specific glutamate receptor called mGluR4.

“Without the committed support of MJFF, it would have been impossible to develop this nascent and high-risk idea,” said Dr. Conn. “Traditional sources of funding for academic research do not provide support for the type of team-based drug discovery efforts that are essential for translating novel ideas into medicines that can help Parkinson’s patients.”

By 2007, Dr. Conn’s team had already produced significant results. That year, MJFF extended and expanded its partnership with Conn, awarding $4.4 million through its LEAPS (Linked Efforts to Accelerate Parkinson’s Solutions) program to investigate mGluR4. Designed with projects like this one in mind, the LEAPS initiative funds “all-star” research teams to tackle important research questions for PD, engaging a collaborative, milestone-driven approach.

By 2009 it appeared that this approach was working: Dr. Conn reported the attainment of a major milestone. His team had discovered systemically active compounds targeting mGluR4. Working in pre-clinical disease models, Dr. Conn had verified that these compounds made it into the brain and went to all the intended places. Crucially, he had also confirmed that the compounds were beneficial in a pre-clinical model of PD. As Chemical & Engineering wrote that year, Conn’s vision was coming to fruition; he had built an operation that resembled “a biotech company operating within the walls of a university.”

In late summer 2011, Conn attained the final stage of pre-clinical testing prior to human trials. The team announced that it was ready to declare drug candidate status on three drug-like molecules acting on mGluR4, with the hope of moving forward to the clinic by 2013. The compounds are known as “positive allosteric modulators,” or PAMs. To increase mGluR4 activity while minimizing the likelihood of adverse effects, Conn’s team has taken a subtle approach to manipulating the mGluR4 receptor. “You can liken it to a dimmer switch on a light in your home, where you can turn up the gain of the receptor and its activity, or turn it down, without completely activating it or shutting it off,” Conn explains.

Typically, the timeline for translating a discovery like Dr. Conn’s into a new treatment for a central nervous system disorder like PD can take as many as 20 years. With MJFF support, Dr. Conn’s group had radically accelerated this process.

“Following the MJFF philosophy,” said Dr. Conn, “we have now de-risked the idea of using mGluR4 for treatment of PD to a point where multiple pharmaceutical companies are now interested in working with us to evaluate this promising new approach.”

– Nate Herpich

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